RU2746129C2 - Биарильные монобактамные соединения и способы их применения для лечения бактериальных инфекций - Google Patents
Биарильные монобактамные соединения и способы их применения для лечения бактериальных инфекций Download PDFInfo
- Publication number
- RU2746129C2 RU2746129C2 RU2018123484A RU2018123484A RU2746129C2 RU 2746129 C2 RU2746129 C2 RU 2746129C2 RU 2018123484 A RU2018123484 A RU 2018123484A RU 2018123484 A RU2018123484 A RU 2018123484A RU 2746129 C2 RU2746129 C2 RU 2746129C2
- Authority
- RU
- Russia
- Prior art keywords
- amino
- dimethyl
- aminothiazol
- imino
- phenoxy
- Prior art date
Links
- 238000000034 method Methods 0.000 title description 115
- 208000035143 Bacterial infection Diseases 0.000 title description 17
- 208000022362 bacterial infectious disease Diseases 0.000 title description 17
- WZPBZJONDBGPKJ-VEHQQRBSSA-N aztreonam Chemical class O=C1N(S([O-])(=O)=O)[C@@H](C)[C@@H]1NC(=O)C(=N/OC(C)(C)C(O)=O)\C1=CSC([NH3+])=N1 WZPBZJONDBGPKJ-VEHQQRBSSA-N 0.000 title description 7
- -1 biaryl monobactam compounds Chemical class 0.000 claims abstract description 591
- 150000001875 compounds Chemical class 0.000 claims abstract description 491
- 150000003839 salts Chemical class 0.000 claims abstract description 189
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims abstract description 165
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 94
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 56
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 56
- 239000001257 hydrogen Substances 0.000 claims abstract description 51
- 125000002950 monocyclic group Chemical group 0.000 claims abstract description 43
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 43
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 40
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 40
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 38
- 150000002367 halogens Chemical class 0.000 claims abstract description 38
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 36
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 32
- 125000003118 aryl group Chemical group 0.000 claims abstract description 28
- 125000006413 ring segment Chemical group 0.000 claims abstract description 28
- 125000001424 substituent group Chemical group 0.000 claims abstract description 27
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 17
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 15
- 125000003831 tetrazolyl group Chemical group 0.000 claims abstract description 10
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 109
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 94
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical group CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 claims description 64
- 125000001841 imino group Chemical group [H]N=* 0.000 claims description 63
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 56
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 50
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 35
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 claims description 35
- 235000019260 propionic acid Nutrition 0.000 claims description 27
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 21
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 20
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 15
- 229910052799 carbon Inorganic materials 0.000 claims description 14
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 239000010802 sludge Substances 0.000 claims description 4
- VXIYDYFOEDTARB-TWCQISOYSA-N [(3S)-3-[[(2Z)-2-[2-[4-[1-(3-aminopropyl)pyrazol-4-yl]phenoxy]ethoxyimino]-2-(2-amino-1,3-thiazol-4-yl)acetyl]amino]-2,2-dimethyl-4-oxoazetidin-1-yl] hydrogen sulfate Chemical compound CC1(C)[C@H](NC(=O)C(=N/OCCOc2ccc(cc2)-c2cnn(CCCN)c2)\c2csc(N)n2)C(=O)N1OS(O)(=O)=O VXIYDYFOEDTARB-TWCQISOYSA-N 0.000 claims description 3
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- AQQBUZOUQXYYIM-LJQANCHMSA-N S(=O)(=O)(ON1C([C@@H](C1=O)NC(C(=NOCCOC1=CC=C(C=C1)C1=NC2=C(CNCC2)N1)C=1N=C(SC=1)N)=O)(C)C)O Chemical compound S(=O)(=O)(ON1C([C@@H](C1=O)NC(C(=NOCCOC1=CC=C(C=C1)C1=NC2=C(CNCC2)N1)C=1N=C(SC=1)N)=O)(C)C)O AQQBUZOUQXYYIM-LJQANCHMSA-N 0.000 claims description 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-O propan-1-aminium Chemical compound CCC[NH3+] WGYKZJWCGVVSQN-UHFFFAOYSA-O 0.000 claims 3
- 229910021653 sulphate ion Inorganic materials 0.000 claims 3
- FVOUYQKJNSWGEP-VGAJERRHSA-N S(=O)(=O)(ON1C([C@@H](C1=O)NC(C(C=1N=C(SC=1)N)=NOCC(C(=O)O)OC1=CC=C(C=C1)C=1C=[N+](N(C=1)CCCN)C)=O)(C)C)[O-] Chemical compound S(=O)(=O)(ON1C([C@@H](C1=O)NC(C(C=1N=C(SC=1)N)=NOCC(C(=O)O)OC1=CC=C(C=C1)C=1C=[N+](N(C=1)CCCN)C)=O)(C)C)[O-] FVOUYQKJNSWGEP-VGAJERRHSA-N 0.000 claims 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 2
- LPNANZKGXXRDNY-CCOBNSAYSA-N (2R,3S)-3-[[(2Z)-2-[(1S)-2-[4-[1-(3-aminopropyl)-2-methylpyrazol-2-ium-4-yl]phenoxy]-1-carboxyethoxy]imino-2-(2-amino-1,3-thiazol-4-yl)acetyl]amino]-2-methyl-4-oxoazetidine-1-sulfonate Chemical compound NCCCN1[N+](=CC(=C1)C1=CC=C(OC[C@H](O\N=C(/C(=O)N[C@H]2[C@H](N(C2=O)S(=O)(=O)[O-])C)\C=2N=C(SC=2)N)C(=O)O)C=C1)C LPNANZKGXXRDNY-CCOBNSAYSA-N 0.000 claims 1
- FIHJSJASOZJUHA-UPKWXMMBSA-N (2S)-3-[4-[2-(3-aminopropylamino)pyridin-4-yl]phenoxy]-2-[(Z)-[1-(2-amino-1,3-thiazol-4-yl)-2-[[(3S)-2,2-dimethyl-4-oxo-1-sulfooxyazetidin-3-yl]amino]-2-oxoethylidene]amino]oxypropanoic acid Chemical compound CC1(C)[C@H](NC(=O)C(=N/O[C@@H](COc2ccc(cc2)-c2ccnc(NCCCN)c2)C(O)=O)\c2csc(N)n2)C(=O)N1OS(O)(=O)=O FIHJSJASOZJUHA-UPKWXMMBSA-N 0.000 claims 1
- LPNANZKGXXRDNY-VXZRKSSRSA-N (2S,3S)-3-[[(2Z)-2-[(1S)-2-[4-[1-(3-aminopropyl)-2-methylpyrazol-2-ium-4-yl]phenoxy]-1-carboxyethoxy]imino-2-(2-amino-1,3-thiazol-4-yl)acetyl]amino]-2-methyl-4-oxoazetidine-1-sulfonate Chemical compound NCCCN1[N+](=CC(=C1)C1=CC=C(OC[C@H](O\N=C(/C(=O)N[C@H]2[C@@H](N(C2=O)S(=O)(=O)[O-])C)\C=2N=C(SC=2)N)C(=O)O)C=C1)C LPNANZKGXXRDNY-VXZRKSSRSA-N 0.000 claims 1
- RVZRLFUMFFBCSC-XCWUCEQJSA-N CC1([C@@H](C(=O)N1OS(=O)(=O)[O-])NC(=O)/C(=N\O[C@@H](COC2=CC=C(C=C2)C3=CN([N+](=C3)C)CCCN)C(=O)O)/C4=CSC(=N4)N)C Chemical compound CC1([C@@H](C(=O)N1OS(=O)(=O)[O-])NC(=O)/C(=N\O[C@@H](COC2=CC=C(C=C2)C3=CN([N+](=C3)C)CCCN)C(=O)O)/C4=CSC(=N4)N)C RVZRLFUMFFBCSC-XCWUCEQJSA-N 0.000 claims 1
- PCDMIQYCVHIQQS-LWMIZPGFSA-N S(=O)(=O)(ON1C([C@@H](C1=O)NC(C(C=1N=C(SC=1)N)=NOC(CCC1=CC=C(C=C1)C=1C=[N+](N(C=1)CCCN)C)C(=O)O)=O)(C)C)[O-] Chemical compound S(=O)(=O)(ON1C([C@@H](C1=O)NC(C(C=1N=C(SC=1)N)=NOC(CCC1=CC=C(C=C1)C=1C=[N+](N(C=1)CCCN)C)C(=O)O)=O)(C)C)[O-] PCDMIQYCVHIQQS-LWMIZPGFSA-N 0.000 claims 1
- BEDZYSJORBFZDP-WWSGVFNASA-N S(=O)(=O)(ON1C([C@@H](C1=O)NC(\C(\C=1N=C(SC1)N)=N/OCCOC=1C=NC(=CC1)N1C=[N+](C=C1)CCCN)=O)(C)C)[O-] Chemical compound S(=O)(=O)(ON1C([C@@H](C1=O)NC(\C(\C=1N=C(SC1)N)=N/OCCOC=1C=NC(=CC1)N1C=[N+](C=C1)CCCN)=O)(C)C)[O-] BEDZYSJORBFZDP-WWSGVFNASA-N 0.000 claims 1
- DDYDRCXJDLEJDH-CQRAGZKESA-N [(3S)-3-[[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-[(1S)-1-carboxy-2-[4-(1-methyl-6-piperazin-1-ylpyridin-1-ium-3-yl)phenoxy]ethoxy]iminoacetyl]amino]-2,2-dimethyl-4-oxoazetidin-1-yl] sulfate Chemical compound S(=O)(=O)(ON1C([C@@H](C1=O)NC(\C(=N/O[C@@H](COC1=CC=C(C=C1)C=1C=[N+](C(=CC=1)N1CCNCC1)C)C(=O)O)\C=1N=C(SC=1)N)=O)(C)C)[O-] DDYDRCXJDLEJDH-CQRAGZKESA-N 0.000 claims 1
- UEFCWYSCDKAJNF-DDXMEKHPSA-N [(3S)-3-[[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-[(1S)-2-[4-[1,2-bis(3-aminopropyl)pyrazol-2-ium-4-yl]phenoxy]-1-carboxyethoxy]iminoacetyl]amino]-2,2-dimethyl-4-oxoazetidin-1-yl] sulfate Chemical compound S(=O)(=O)(ON1C([C@@H](C1=O)NC(\C(=N/O[C@@H](COC1=CC=C(C=C1)C=1C=[N+](N(C=1)CCCN)CCCN)C(=O)O)\C=1N=C(SC=1)N)=O)(C)C)[O-] UEFCWYSCDKAJNF-DDXMEKHPSA-N 0.000 claims 1
- RHZGWQHWRRKXSX-HSGFMCRSSA-N [(3S)-3-[[(2Z)-2-[(1S)-2-[4-[1-(2-aminoethyl)-2-methylpyrazol-2-ium-4-yl]phenoxy]-1-carboxyethoxy]imino-2-(2-amino-1,3-thiazol-4-yl)acetyl]amino]-2,2-dimethyl-4-oxoazetidin-1-yl] sulfate Chemical compound S(=O)(=O)(ON1C([C@@H](C1=O)NC(\C(\C=1N=C(SC=1)N)=N/O[C@@H](COC1=CC=C(C=C1)C=1C=[N+](N(C=1)CCN)C)C(=O)O)=O)(C)C)[O-] RHZGWQHWRRKXSX-HSGFMCRSSA-N 0.000 claims 1
- NNJWNLRZVNBWMY-ZUJBQOBQSA-N [(3S)-3-[[(2Z)-2-[(1S)-2-[4-[6-(3-aminopropyl)-1-methylpyridin-1-ium-3-yl]phenoxy]-1-carboxyethoxy]imino-2-(2-amino-1,3-thiazol-4-yl)acetyl]amino]-2,2-dimethyl-4-oxoazetidin-1-yl] sulfate Chemical compound C[n+]1cc(ccc1CCCN)-c1ccc(OC[C@H](O\N=C(/C(=O)N[C@@H]2C(=O)N(OS([O-])(=O)=O)C2(C)C)c2csc(N)n2)C(O)=O)cc1 NNJWNLRZVNBWMY-ZUJBQOBQSA-N 0.000 claims 1
- CUFPMNDJFYKFNP-BFDAQVDISA-N [(3S)-3-[[(2Z)-2-[2-[4-[1-(3-aminopropyl)-2-methylpyrazol-2-ium-4-yl]phenoxy]ethoxyimino]-2-(2-amino-1,3-thiazol-4-yl)acetyl]amino]-2,2-dimethyl-4-oxoazetidin-1-yl] sulfate Chemical compound S(=O)(=O)(ON1C([C@@H](C1=O)NC(\C(\C=1N=C(SC=1)N)=N/OCCOC1=CC=C(C=C1)C=1C=[N+](N(C=1)CCCN)C)=O)(C)C)[O-] CUFPMNDJFYKFNP-BFDAQVDISA-N 0.000 claims 1
- TUEVQPUBMYVDSI-UHFFFAOYSA-N pyridin-1-ium 2,2,2-trifluoroacetate Chemical compound C1=CC=[NH+]C=C1.C1=CC=[NH+]C=C1.[O-]C(=O)C(F)(F)F.[O-]C(=O)C(F)(F)F TUEVQPUBMYVDSI-UHFFFAOYSA-N 0.000 claims 1
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 abstract description 30
- 239000003814 drug Substances 0.000 abstract description 18
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 abstract description 14
- 239000000126 substance Substances 0.000 abstract description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 abstract description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract description 5
- 230000000694 effects Effects 0.000 abstract description 4
- 229910052740 iodine Inorganic materials 0.000 abstract description 3
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 abstract 1
- 230000001747 exhibiting effect Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 368
- 239000000243 solution Substances 0.000 description 267
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical group CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 253
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 227
- 239000000203 mixture Substances 0.000 description 215
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 186
- 239000011541 reaction mixture Substances 0.000 description 173
- 235000019439 ethyl acetate Nutrition 0.000 description 168
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 132
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 114
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 111
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 100
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 97
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 87
- XZLRJCSXDLXBSC-UHFFFAOYSA-N 3-[(2-methylpropan-2-yl)oxycarbonylamino]propyl 2-cyanoacetate Chemical group CC(C)(C)OC(=O)NCCCOC(=O)CC#N XZLRJCSXDLXBSC-UHFFFAOYSA-N 0.000 description 85
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 80
- 239000000460 chlorine Substances 0.000 description 77
- 239000000741 silica gel Substances 0.000 description 75
- 229910002027 silica gel Inorganic materials 0.000 description 75
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 57
- 239000012044 organic layer Substances 0.000 description 54
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 53
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 52
- 239000012267 brine Substances 0.000 description 49
- 239000000706 filtrate Substances 0.000 description 49
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 49
- 239000003480 eluent Substances 0.000 description 46
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 40
- 239000002904 solvent Substances 0.000 description 40
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 34
- 238000005160 1H NMR spectroscopy Methods 0.000 description 33
- 239000011734 sodium Substances 0.000 description 33
- 238000004440 column chromatography Methods 0.000 description 32
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 32
- 239000000543 intermediate Substances 0.000 description 30
- 239000012071 phase Substances 0.000 description 30
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 29
- 229910052737 gold Inorganic materials 0.000 description 29
- 239000010931 gold Substances 0.000 description 29
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 29
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 28
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 28
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 27
- 238000002360 preparation method Methods 0.000 description 26
- 238000005481 NMR spectroscopy Methods 0.000 description 25
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 24
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 23
- CDGJTKZKKHLQQN-GSVOUGTGSA-N [(3s)-3-amino-2,2-dimethyl-4-oxoazetidin-1-yl] hydrogen sulfate Chemical compound CC1(C)[C@H](N)C(=O)N1OS(O)(=O)=O CDGJTKZKKHLQQN-GSVOUGTGSA-N 0.000 description 23
- 238000010898 silica gel chromatography Methods 0.000 description 23
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 20
- 238000006243 chemical reaction Methods 0.000 description 20
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 20
- 235000017557 sodium bicarbonate Nutrition 0.000 description 20
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 19
- 102000006635 beta-lactamase Human genes 0.000 description 19
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 19
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 125000005336 allyloxy group Chemical group 0.000 description 18
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 18
- 239000010410 layer Substances 0.000 description 18
- CFMZSMGAMPBRBE-UHFFFAOYSA-N 2-hydroxyisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(O)C(=O)C2=C1 CFMZSMGAMPBRBE-UHFFFAOYSA-N 0.000 description 17
- 239000003781 beta lactamase inhibitor Substances 0.000 description 17
- 229940126813 beta-lactamase inhibitor Drugs 0.000 description 17
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 17
- 241000894006 Bacteria Species 0.000 description 16
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 16
- 230000002441 reversible effect Effects 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 239000003153 chemical reaction reagent Substances 0.000 description 15
- 235000019253 formic acid Nutrition 0.000 description 15
- 238000004007 reversed phase HPLC Methods 0.000 description 15
- 239000007787 solid Substances 0.000 description 15
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 15
- 229940126085 β‑Lactamase Inhibitor Drugs 0.000 description 15
- LDTMNHIZDFDFFY-UHFFFAOYSA-N 2-[2-[(2-methylpropan-2-yl)oxycarbonylamino]-1,3-thiazol-4-yl]-2-oxoacetic acid Chemical compound CC(C)(C)OC(=O)NC1=NC(C(=O)C(O)=O)=CS1 LDTMNHIZDFDFFY-UHFFFAOYSA-N 0.000 description 14
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 14
- 125000001072 heteroaryl group Chemical group 0.000 description 14
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- 238000005406 washing Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 238000002424 x-ray crystallography Methods 0.000 description 1
- 150000003954 δ-lactams Chemical class 0.000 description 1
Classifications
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
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- A61K31/433—Thidiazoles
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A—HUMAN NECESSITIES
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- A—HUMAN NECESSITIES
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
- C07C53/15—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen containing halogen
- C07C53/16—Halogenated acetic acids
- C07C53/18—Halogenated acetic acids containing fluorine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
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- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/424—Oxazoles condensed with heterocyclic ring systems, e.g. clavulanic acid
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
- A61K31/431—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems containing further heterocyclic rings, e.g. ticarcillin, azlocillin, oxacillin
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
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PL2790681T5 (pl) | 2011-11-18 | 2024-02-05 | Regeneron Pharmaceuticals, Inc. | Sposób otrzymywania farmaceutycznej postaci użytkowej o przedłużonym uwalnianiu zawierającej mikrocząstki białkowe powlekane polimerem z wykorzystaniem suszenia rozpyłowego |
MX2017016424A (es) | 2015-06-15 | 2019-08-01 | Nmd Pharma Aps | Compuestos para su uso en el tratamiento de trastornos neuromusculares. |
RU2746129C2 (ru) | 2015-12-15 | 2021-04-07 | Мерк Шарп И Доум Корп. | Биарильные монобактамные соединения и способы их применения для лечения бактериальных инфекций |
EP3691639B1 (en) | 2017-10-02 | 2023-11-15 | Merck Sharp & Dohme LLC | Chromane monobactam compounds for the treatment of bacterial infections |
US11591284B2 (en) | 2017-12-14 | 2023-02-28 | Nmd Pharma A/S | Compounds for the treatment of neuromuscular disorders |
US11730714B2 (en) | 2017-12-14 | 2023-08-22 | Nmd Pharma A/S | Compounds for the treatment of neuromuscular disorders |
US11147788B2 (en) | 2017-12-14 | 2021-10-19 | Nmd Pharma A/S | Compounds for the treatment of neuromuscular disorders |
US10385028B2 (en) | 2017-12-14 | 2019-08-20 | Nmd Pharma A/S | Compounds for the treatment of neuromuscular disorders |
CN108362789B (zh) * | 2018-01-19 | 2020-09-01 | 珠海优润医药科技有限公司 | 一种阿维巴坦钠光学异构体的高效液相色谱检测方法 |
CN111511737B (zh) * | 2018-01-29 | 2022-10-18 | 南京明德新药研发有限公司 | 用于治疗细菌感染的单环β-内酰胺化合物 |
WO2020048828A1 (en) | 2018-09-03 | 2020-03-12 | Bayer Pharma Aktiengesellschaft | 5-heteroaryl-3,9-diazaspiro[5.5]undecane compounds |
WO2020048827A1 (en) | 2018-09-03 | 2020-03-12 | Bayer Aktiengesellschaft | 1, 3, 9-triazaspiro[5.5] undecan-2-one compounds |
US20220002288A1 (en) * | 2018-11-13 | 2022-01-06 | Nanjing Sanhome Pharmaceutical Co., Ltd. | Monobactam compounds and use therefor |
CA3121202A1 (en) | 2018-11-30 | 2020-06-04 | Nuvation Bio Inc. | Pyrrole and pyrazole compounds and methods of use thereof |
CN111303144B (zh) * | 2019-12-13 | 2020-11-27 | 苏州信诺维医药科技有限公司 | 一种治疗细菌感染的化合物 |
EP4079305A4 (en) * | 2019-12-19 | 2024-01-10 | Shenzhen Optimum Biological Technology Co., Ltd | APPLICATION OF A COMPOUND IN THE PREPARATION OF DRUG |
WO2022027439A1 (en) * | 2020-08-06 | 2022-02-10 | Ningxia Academy Of Agriculture And Forestry Sciences | β-LACTAM COMPOUNDS, THEIR PREPARATION AND USE AS ANTIBACTERIAL AGENTS |
CN112661667B (zh) * | 2020-12-28 | 2023-02-03 | 浦拉司科技(上海)有限责任公司 | 一种三氟乙脒的制备方法 |
CN115463219A (zh) * | 2021-11-09 | 2022-12-13 | 中国医学科学院医药生物技术研究所 | 包含β-内酰胺类化合物的药物组合物及其用途 |
IL312841A (en) | 2021-11-18 | 2024-07-01 | Merck Sharp & Dohme Llc | CHROMANE AMIDINE MONOBACTAM ANTIBIOTICS |
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EA201400838A1 (ru) * | 2012-01-24 | 2014-12-30 | Аикурис Гмбх Унд Ко. Кг | ЗАМЕЩЕННЫЕ АМИДИНОМ β-ЛАКТАМЫ, ИХ ПОЛУЧЕНИЕ И ПРИМЕНЕНИЕ В КАЧЕСТВЕ АНТИБАКТЕРИАЛЬНЫХ СРЕДСТВ |
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RU2746129C2 (ru) | 2015-12-15 | 2021-04-07 | Мерк Шарп И Доум Корп. | Биарильные монобактамные соединения и способы их применения для лечения бактериальных инфекций |
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2020
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WO2017106064A1 (en) | 2017-06-22 |
AU2016371600A1 (en) | 2018-05-10 |
BR112018010962A8 (pt) | 2023-04-11 |
EP3390357A1 (en) | 2018-10-24 |
US11230543B2 (en) | 2022-01-25 |
MA44083A (fr) | 2021-06-02 |
BR112018010962A2 (pt) | 2018-12-04 |
JP7184646B2 (ja) | 2022-12-06 |
US20200361928A1 (en) | 2020-11-19 |
RU2018123484A (ru) | 2020-01-17 |
CN108368040A (zh) | 2018-08-03 |
EP3978472A1 (en) | 2022-04-06 |
KR20180093925A (ko) | 2018-08-22 |
MX2018005382A (es) | 2018-08-16 |
CN108368040B (zh) | 2024-08-23 |
AU2016371600B2 (en) | 2021-02-18 |
RU2018123484A3 (pt) | 2020-03-26 |
JP2018537483A (ja) | 2018-12-20 |
EP3390357B1 (en) | 2021-11-10 |
CA3008006A1 (en) | 2017-06-22 |
US20180339983A1 (en) | 2018-11-29 |
CA3008006C (en) | 2024-04-09 |
EP3390357A4 (en) | 2019-06-12 |
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